Design, synthesis, and structure-activity relationships of the first highly potent, selective, and bioavailable adenosine 5'-monophosphate deaminase inhibitors

• Published in: Advances in experimental medicine and biology Vol. 431; p. 849
• Main Authors: Kasibhatla, S R, Bookser, B C, Appleman, J R, Probst, G, Xiao, W, Fujitaki, J M, Erion, M D
• Format: Journal Article
• Language: English
• Published: United States 1998
• Subjects: Adenine - analogs & derivatives; Adenine - chemical synthesis; Adenine - chemistry; Adenine - pharmacokinetics; Adenosine Monophosphate - chemistry; Administration, Oral; AMP Deaminase - antagonists & inhibitors; Biological Availability; Coformycin - analogs & derivatives; Coformycin - chemical synthesis; Coformycin - chemistry; Coformycin - pharmacokinetics; Drug Design; Entropy; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Humans; Models, Molecular; Molecular Conformation; Molecular Structure; Structure-Activity Relationship
• ISSN: 0065-2598
• DOI: 10.1007/978-1-4615-5381-6_163

Structure-activity studies have been performed to optimize the potency of this novel series of AMPDA inhibitors. Conformational rigidification of the N-3 sidechain resulted in substantial effect on the potency. Addition of the hydrophobic groups provided further benefit. The most potent compound identified, 4g (Ki = 3 nM), bears little structural resemblance to AMP and exhibits a remarkable improvement (10(3) and 10(5)) in binding affinity relative to the original lead and AMP, respectively. The application of prodrug strategy achieved a large improvement (benzyl ester 5d) in oral bioavailability, resulting in compounds that should be useful in evaluating the role of AMPDA in normo- and pathophysiological states.